Method of Treating Fibromyalgia or Associated Functional Symptoms of Fibromyalgia

ABSTRACT

The invention relates to a method of treating fibromyalgia or associated functional symptoms of fibromyalgia using a 1-acylpiperidine substance P antagonist, the 1-acylpiperidine substance P antagonist comprising a compound of formula 
     
       
         
         
             
             
         
       
     
     wherein X and Y are each independent of the other N and/or CH, and the ring A is unsubstituted or mono- or poly-substituted by substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, nitro and trifluoromethyl and for each compound, pharmaceutically-acceptable salts thereof.

This application is a continuation of application Ser. No. 12/008,777filed on 14 Jan. 2008, which is a continuation of application Ser. No.11/715,805 filed on 8 Mar. 2007, abandoned, which is a continuation ofapplication Ser. No. 10/947,967 filed on 23 Sep. 2004, abandoned, whichis a continuation of application Ser. No. 10/222,060 filed on 16 Aug.2002, abandoned, which is a continuation of application Ser. No.09/792,801 filed 23 Feb. 2001, abandoned, which is a continuation ofInternational Application No. PCT/EP99/06215 filed on 24 Aug. 1999, theentire disclosures of which are hereby incorporated by reference.

This invention relates to substance P antagonists, in particular to1-acylpiperidine substance P antagonists, and more specifically to newpharmaceuticals uses of such compounds.

Substance P antagonists and their pharmaceutical use for treatment ofgastrointestinal disorders, inflammatory disorders, central nervoussystem disorders and pain are described in, for instance, WO 90/05525,WO 91/09844 and WO 91/18899. 1-acylpiperidines and more particularlyN-benzoyl-2-benzyl-4-azanaphthoyl-amino piperidines and their activitiesas substance P antagonists are described in European patent EP 0532456 Band published European patent application EP 0739892 A and Europeanpatent EP 0707006 B respectively. The disclosures of EP 0532456 B, EP0707006 B and EP 0739892 A are incorporated by reference in the teachingof the present application.

WO 96/24353 (Eli Lilly) describes a method for the treatment andprevention of a psychiatric disorder in a mammal which comprisesadministering to a mammal in need thereof an effective amount of acombination of a tachykinin receptor antagonist and either a serotoninagonist or a selective serotonin reuptake inhibitor. Chronic fatiguesyndrome is listed amongst the numerous psychiatric disorders which areidentified as candidates for treatment by this method.

Similarly WO 97/38692 (Eli Lilly) relates to a series of bisindoleswhich have activity both as tachykinin receptor antagonists and asserotonin agonists, and describes use of these bisindoles to treatmigraine, pain or nociception, allergic rhinitis, the common cold, and avariety of psychiatric disorders including chronic fatigue syndromeamongst many others.

Surprisingly it has now been found that substance P antagonists, inparticular 1-acylpiperidines and especiallyN-benzoyl-2-benzyl-4-(azanaphthoyl-amino) piperidines, andpharmaceutically acceptable salts thereof are particularly useful fortreatment of chronic fatigue syndrome in the absence of serotoninagonist/selective serotonin reuptake inhibitory therapy.

Chronic fatigue disorders are a poorly defined clinical syndrome orcombination of syndromes characterised by complaints of excessivefatigue and neurophysiological disturbances, often beginning after aviral infection. Attempts have been made to define diagnostic criteriafor Chronic Fatigue Syndrome (CFS) but until recently the diagnosis hasremained based on purely subjective criteria (Holmes et al. Annals ofInternal Medicine 108: 387-389 (1988); Fukuda et al. Annals of InternalMedicine 121: 953-959 (1994)). In general, the fatigue is felt to beexacerbated following physical exertion, emotional stress, and/or viralillnesses. Lightheadedness, difficulty with thinking or concentrating,sleep disturbances, diffuse joint pain and tenderness, depression andweight fluctuations are often concurrent clinical features of chronicfatigue disorders. This general syndrome of chronic fatigue has alsobeen designated CFS, neurasthenia, myalgic encephalomyelitis,fibromyalgia, post-viral syndrome, and chronic fatigue and immunedysfunction syndrome (CFIDS) (Price et al. Public Health Reports 107:514-522 (1992)).

Considerable uncertainty exists concerning the etiological basis of thisconstellation of symptoms. There are few consistent objective clinicalfindings in the disorder except that it is more prevalent in femalesthan in males (Price et al. Public Health Reports 107: 514-522 (1992);Bou-Hlaigah et al. JAMA 274: 961-967 (1995)).

Recently molecular genetic analysis has been applied to CFS (WO98/37239—Glaxo) and it has been found that allelic variations within thearginine-vasopressin receptor-2 (AVPR2) gene are associated withvariations in the clinical susceptibility to chronic fatigue disordersand this provides new methods for diagnosing CFS. These methods aredescribed in WO 98/37239.

Substance P antagonists for use in the invention for treatment of CFSare 1-acylpiperidines and more particularlyN-benzoyl-2-benzyl-4-azanaphthoyl-amino piperidines; for instance asdescribed in EP 0532456 B, EP 0707006 B and EP 0739892 A.

Surprisingly it has also now been found that 1-acylpiperidine substanceP antagonists, especially N-benzoyl-2-benzyl-4-(azanaphthoyl-amino)piperidines, and pharmaceutically acceptable salts thereof areparticularly useful for treatment of fibromyalgia or associatedfunctional symptoms of fibromyalgia.

Accordingly the present invention provides the use of a 1-acylpiperidinesubstance P antagonist or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for treatment of CFS, or fibromyalgia orassociated functional symptoms of fibromyalgia.

Fibromyalgia is a disease characterized by widespread musculoskeletalpain and tenderness on palpation at so called tenderpoints. The diseaseis diagnosed according to criteria as defined by the American College ofRheumatology (ACR) [see Arthritis and Rheumatism, Vol. 33, No. 2, pages160-172, 1990]. In addition to pain symptoms, in the majority offibromyalgia patients a variety of functional symptoms such as headache,insomnia, irritable bowel syndrome, sicca symptoms, increased sweating,dizziness, tremor, dyspnoea, arrhythmias, paraesthesias,headache/migraine, fatigue, psychopathological disorders and othersoccur. Therefore, the medical approaches towards management offibromyalgia should not exclusively aim at relief of pain symptoms butalso aim at improvements in functional symptoms.

The present invention is to be understood as embracing the treatment offibromyalgia as such, as well as pain and/or functional symptomsassociated with fibromyalgia either individually or collectively, e.g.use of 1-acylpiperidine substance P antagonists for treatment, e.g. thealleviation or amelioration of pain or any of the above mentionedsymptoms as components of fibromyalgia. In addition to pain relief infibromyalgia the present invention in particular provides for thetreatment of the following functional symptoms as associated withfibromyalgia: including headache, insomnia, irritable bowel syndrome,sicca symptoms, increased sweating, dizziness, tremor, dyspnoea,arrhythmias, paraesthesias, headache/migraine, fatigue andpsychopathological disorders.

1-Acylpiperidine substance P antagonists are hereinafter referred to asPreferred Compounds of the Invention.

The Preferred Compounds of the Invention include in particular the1-acylpiperidine substance P antagonists as described and claimed in EP0532456 B. The Preferred Compounds of the Invention are convenientlyused as mono-therapy for the treatment of CFS.

Particularly preferred Compounds of the Invention are the compounds ofEP 0739892 A, e.g. the compounds:

-   (2R,4S)-N-[1-(3,5-bisfluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]-4-oxo-4H-1-benzopyran-2-carboxamide;-   (2R,4S)-N-[1-(3,5-bisfluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-4-oxo-4H-1-benzopyran-2-carboxamide,    and-   (2R,4S)-N-[1-(3,5-bisfluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]-6-fluoro-4-oxo-4H-l-benzopyran-2-carboxamide,    and pharmaceutically acceptable salts thereof; and especially the    compounds of EP 0707006 B, i.e. of formula I

wherein X and Y are each independently of the other N and/or CH and thering A is unsubstituted or mono- or poly-substituted by substituentsselected from the group consisting of lower alkyl, lower alkoxy,halogen, nitro and trifluoromethyl; and pharmaceutically acceptablesalts thereof, e.g. the compounds:

-   (2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-quinoline-4-carboxamide;-   (2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-quinazoline-4-carboxamide;-   (2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-quinoline-4-carboxamide;-   (2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidinyl]-quinazoline-4-carboxamide;-   (2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidinyl]-isoquinoline-1-carboxamide;-   (2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-nitro-benzyl)-piperidinyl]-quinazoline-4-carboxamide;    or in each case a salt thereof.

Suitable pharmaceutically acceptable salts, e.g. for oraladministration, are described in EP 0707006B.

Preference is given to compounds of formula I wherein the ring A issubstituted. The invention relates especially to the use of compounds offormula IA

wherein X is CH or N and Y is N, and Z is hydrogen, halogen or nitro,and to the pharmaceutically acceptable salts thereof.

The invention relates more especially to use of compounds of formula IAwherein X is N or CH and Y is N, and Z is halogen, such as chlorine, andto the pharmaceutically acceptable salts thereof.

Most especially the invention relates to the use of the compound(2R,4S)-N-[1-(3,5-bistrifluoromethylbenzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl-quinolin-4-carboxamide,and to the pharmaceutically acceptable salts thereof.

Unless otherwise defined, the general terms used hereinbefore andhereinafter have the meanings given in EP 0707006 B.

The usefulness of the Preferred Compounds of the Invention, fortreatment of Chronic Fatigue Syndrome (CFS) is demonstrated in thefollowing clinical study.

CFS Clinical Study Patient Population

Patients with chronic fatigue syndrome according to the CDC (Centre forDisease Control) definition (G. P. Holmes et al.: A working casedefinition. Ann. intern. Med; 108 (1988), 387-389) are included in thetrial. Other recognized definitions may be used to identify patientswith chronic fatigue syndrome as appropriate. Both male and femalepatients are eligible, provided they are over 18 years of age and under65 years of age. The main exclusion criteria comprise pregnant andlactating women; in addition patients suffering from other diseases thatcause significant fatigue as well as patients who suffer from activeinfections are excluded. Other exclusion criteria comprise severerheumatological diseases, severe neuropathies, clinically manifestendocrinopathies, psychiatric diseases (including depression),fibromyalgia, and severe cardial, renal and hepatic impairment.

The study is in the form of a prospective, randomized, double-blind,placebo-controlled, parallel-group study using different doses of aPreferred Compound of the Invention, (e.g.(2R,4S)-N-[1-(3,5-bistrifluoromethylbenzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl-quinolin-4-carboxamide).Patients are randomly assigned to one of five study arms: placebo, 1 mg,5 mg, 10 mg and 20 mg of test compound. (Preferably, for reliableevaluation of efficacy, each study arm includes 30 patients, giving atotal sample size of 150 patients for the complete study.) The durationof treatment is four weeks. Before, on days 7, 14 and 21 and at the endof the treatment phase, a physical examination as well as assessment offatigue and other symptoms are performed. Before study entry and at theend of the treatment blood tests are carried out. In order to documentthe daily intensity of fatigue, adverse events and concomitantmedications, patients use a standardized diary and record daily theparameters mentioned. In addition, other symptoms as mentioned above,which are associated with CFS such as functional symptoms or cognitiveimpairment and myalgias are documented at start of treatment, and ondays 7, 14, 21 and at the end of treatment. Adverse events are assessedduring the active treatment period.

Regarding changes in fatigue, a visual analog scale is used. This analogscale is represented by a 100-mm-line with one end (=0) indicating “nofatigue” and the other end (=100) indicating “worst fatigue”. Patientsare asked to make a mark on the 100 mm scale which corresponds to theircurrent fatigue intensity.

Other parameters which are evaluated include cognitive impairment (to bemeasured by visual analog scale [VAS]) and the assessment of myalgias.In the latter case a VAS is also used for evaluation; for instance, asdescribed above for assessment of fatigue, in addition to use of a painscore. The pain score allows an assessment of different body regions andranges from 0 to 120, measuring the pain intensity in a total of 24 bodyregions. The following rating scale is applied: 0=no pain, 1=mild pain,2=moderate pain, 3=moderately severe pain, 4=severe pain, 5=most severepain. The assessment of each body region is done by the patientsthemselves; the total score is calculated as the sum of the regionalscores.

The following functional symptoms are evaluated in detail: coldhands/feet, sicca symptoms, increased sweating, dizziness, tremor,difficulties in falling asleep, difficulties in sleeping through,gastric problems, symptoms of irritable bowel syndrome, problems withswallowing, dyspnoea, arrhythmias, paraesthesias, painful micturation,headache/migraine, and morning stiffness. For each of the symptomsmentioned, patients are asked to rate the presence of the symptomsaccording to a score ranging from 0 to 3 (0=not present, 1=slightlypresent, 2=moderately present, 3=strongly present).

In addition to the documented effects during the active treatment phase,a follow-up of the patients is performed for six months in order toevaluate the duration of the clinical response (as defined by a 20% orhigher reduction in any of the following symptoms: fatigue, myalgias,cognitive impairment; comparison of baseline vs. end of treatment).

Up to now there has been no standard or effective treatment for chronicfatigue syndrome. Thus it is proposed that a Compound of the Inventionis considered as effective in treatment of CFS if one or more doses ofthe Compound leads to a response rate at least 10% higher as compared toplacebo, wherein the response rate is the clinical response rate asdefined above.

The usefulness of the Preferred Compounds of the Invention for treatmentof fibromyalgia or associated functional symptoms is demonstrated in thefollowing clinical study.

Fibromyalgia Clinical Study

The study is in the form of a prospective, randomized, double-blind,placebo-controlled, parallel-group study using different doses ofCompound of the Invention. Male and female patients (over 18 years) whomeet the ACR (American College of Rheumatology) criteria for primaryfibromyalgia are included in this trial. The main exclusion criteriainclude pregnant and lactating woman, patients suffering from otherinflammatory rheumatological diseases (such as rheumatoid arthritis orcollagenoses), severe neuropathies, clinically manifestendocrinopathies, bone diseases, severe cardial, renal or hepaticimpairment and acute or chronic infections.

Patients are randomly assigned to one of five study arms, placebo, 1 mg,10 mg, 20 mg and 40 mg of test compound. The duration of treatment istwo weeks. Before, on day 7 and at the end of the treatment phase, aphysical examination, pain assessment and blood testing are performed.In order to document daily the intensity of pain, adverse events andconcomitant medications, patients use a standardized diary and recorddaily the parameters mentioned. In addition, changes in functionalsymptoms are documented at start of treatment, on day 7 and at the endof treatment. Adverse events are assessed during the active treatmentperiod.

To evaluate pain, the pain score, a visual analogue scale and clinicalexamination of tenderpoints is used. The pain score ranges from 0 to120, measuring the pain intensity in 24 body regions applied to thefollowing rating scale: 0=no pain, 1=mild pain, 2=moderate pain,3=moderately severe pain, 4=severe pain, 5=most ever pain. Theassessment of each body region is done by the patients themselves; thetotal score is calculated as the sum of the regional scores.

The visual analogue scale is in the form of 100-mm-line orientedhorizontally with one end=0, indicating “no pain” and the other end=100,indicating “worst pain”. The patients are asked to place a markcorresponding to their perception of their present pain intensity.

In addition to the documented effects during the active treatment phase,a follow-up of the patients is performed for six months in order toevaluate the duration of the clinical response (as defined by a 35% orhigher reduction in individual pain score/baseline versus end oftreatment).

Amitryptilin, an antidepressant drug, is regarded an effective treatmentin fibromyalgia and leads to response rates of about 20 to 30% ofpatients.

For use in accordance with the invention Preferred Compounds of theInvention most suitably are administered to human patients at a dose ofabout 1 to about 40 mg/kg per day. The Preferred Compounds of theInvention may be administered suitably in unit dosage form; forinstance, in divided doses 1 to 5 times daily depending on theparticular purpose of therapy, the phase of therapy and the like.

Suitable dosage form for use in accordance with the invention includeforms for enteral, for example oral, or parenteral administration. Thus,tablets or gelatin capsules which have the active substance togetherwith diluents, for example lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or lubricants, for example diatomaceous earth,talc, stearic acid or salts thereof, such as magnesium or calciumstearate, and/or polyethylene glycol may be used. Tablets may likewisehave binders, for example magnesium aluminum silicate, starches such asmaize, wheat rice or arrowroot starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone and, if required, disintegrants, for examplestarches, agar, alginic acid or a salt thereof, for example sodiumalginate and/or effervescent mixtures, or absorbents, dyes, flavouringsand sweeteners. It is furthermore possible for the Compounds of theInvention to be used in the form of products which can be administeredparenterally or of infusion solutions. Solutions of this type arepreferably isotonic aqueous solutions or suspensions, it being possibleto prepare the latter, for example in the case of lyophilized productswhich comprise the active substance alone or together with an excipient,for example mannitol, before use. The pharmaceutical products can besterilized and/or comprise ancillary substances, for examplepreservatives, stabilizers, wetting agents and/or emulsifiers,solubilizers, salts to control the osmotic pressure and/or buffers. Thepresent pharmaceutical products which, if required, may comprise furtherpharmacologically active substance, are produced in an manner known perse, for example by conventional mixing, granulating, coating, dissolvingor lyophilizing processes, and comprise from about 0.1% to 100%, inparticular from about 1% to about 50%, lyophilizates up to about 100%,of the active substance.

Preferred pharmaceutical compositions comprising the Preferred Compoundsof the invention are spontaneously dispersible pharmaceuticalcompositions, for instance as described in our copending Internationalpatent application PCT/EP 99/03623. The disclosure of Internationalpatent application PCT/EP 99/03623 is incorporated by reference in theteaching of the present application. Specific preferred compositions aredescribed in Examples 4 to 11.

Substance P antagonists are known in the art and may be prepared orobtained by methods known in the art; for instance, as described in EP0532456B, EP 0707006 B and EP 0739892 A for Preferred Compounds of theInvention.

EXAMPLES Example 1

Tablets, each comprising e.g. 50 mg ofbistrifluoromethylbenzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl-quinolin-4-carboxamideor a pharmaceutically acceptable salt, for example the dihydrochloride,thereof, can be prepared as follows:

Composition (10000 tablets) active ingredient 500.0 g lactose 500.0 gpotato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0g silicon dioxide (highly dispersed) 20.0 g ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potatostarch and the mixture is moistened with an ethanolic solution of thegelatin and granulated through a sieve. After drying, the remainder ofthe potato starch, the magnesium stearate, the talc and the silicondioxide are mixed in and the mixture is compressed to form tablets, eachweighing 145.0 mg and comprising 50.0 mg of active ingredient; thetablets may, if desired, be provided with breaking notches for fineradaptation of the dose.

Example 2

Film-coated tablet, each comprising 100 mg of(2R,4S)-N-[l-(3,5-bistrifluoromethylbenzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl-quinolin-4-carboxamideor a pharmaceutically acceptable salt, for example the dihydrochloride,thereof, can be prepared as follows:

Composition (for 1000 film-coated tablets) active ingredient 100.0 glactose 100.0 g corn starch 70.0 g talc 60.0 g calcium stearate 1.5 ghydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s. methylenechloride q.s.

The active ingredient, the lactose and 40 g of the corn starch are mixedand moistened with a paste prepared from 15 g of corn starch and water(with heating) and granulated. The granules are dried, the remainder ofthe corn starch, the talcum and the calcium stearate are added and mixedwith the granules. The mixture is compressed to form tablets (weight:280 mg) which are then film-coated with a solution of thehydroxypropylmethylcellulose and the shellac in methylene chloride;final weight of the film-coated tablet: 283 mg.

Example 3

Hard gelatin capsules, comprising 100 mg of active ingredient, forexample(2R,4S)-N-[1-(3,5-bistrifluoromethylbenzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl-quinolin-4-carboxamideor a pharmaceutically acceptable salt, for example the dihydrochloride,thereof, can be prepared, for example, as follows:

Composition (for 1000 capsules′) active ingredient 100.0 g lactose 250.0g microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 gmagnesium stearate 8.0 g

The sodium lauryl sulfate is added to the lyophilized active ingredientthrough a sieve of 0.2 mm mesh size. The two components are intimatelymixed. Then first the lactose is added through a sieve of 0.6 mm meshsize and then the microcrystalline cellulose is added through a sieve of0.9 mm mesh size. The mixture is then intimately mixed again for 10minutes. Finally the magnesium stearate is added through a sieve of 0.8mm mesh size. After mixing for a further 3 minutes, size 0 hard gelatincapsules are each filled with 390 mg of the resulting formulation. Softgelatin capsules may be prepared using similar ingredients andprocedures.

Preferred compositions are described by way of illustration only in thefollowing Examples, 4 to 11. Unless otherwise indicated, components areshown in % by weight based on each composition. Mean particle sizes(diameters) are measured at 20° C. using a Malvern Zetasizer.

All ingredients of the Examples are given in mg/capsule.

Ex 4a¹ Ex 4b¹ Ex 5² Ex 6² Ex 7² Ex 8² Ex 9² Ex 10² Ex 11² Active AgentCompound A 5.0 1.0 1.0 5.0 1.0 10.0 7.5 17.0 14.0 1) SurfactantCremophor RH 40 232.0 232.0 269.0 225.0 180.0 200.0 200.0 Tween 80 269.0269.0 2) Hydrophilic component Propylene carbonate 25.0 50.0 Caprylicacid 50.0 Triethyl citrate 45.0 50.0 Propylene glycol 46.5 46.5 90.045.0 Polyethylene glycol 400 90.0 90.0 Dimethyl isosorbide 50.0 Labrafil2125 90.0 90.0 Caprylic/capric acid 170.0 218.5 glycerides (Capmul MCM)Propyleneglycol monocaprylate 133.0 136.0 Miglyol 812 refined corn oil³185.0 185.0 90.0 4) Hydrophilic co-component Ethanol abs 52.0 52.0 50.050.0 50.0 50.0 50.0 50.0 50.0 Additive 0 DL-alpha tocopherol 0.5 0.5TOTAL 504.0 500.0 500.0 504.0 500.0 500.0 500.0 500.0 500.0 meanparticle size (nm) 80-90 80-90 20-30 135-145 25-35 — — — — ¹Compound Ais dissolved in (1) with stirring at room temperature and (2) and (3)are added to the obtained solution again with stirring. 0.5 ml portionsof the obtained mixture are filled into size 1 hard gelatine capsulesand sealed, e.g. using the QualiSeal technique, or into soft gelatinecapsules. In another embodiment of Examples 1a and 1b, Compound A isdispersed in a mixture of components 1), 2) and 3), and combined withcomponent 4). ²The carrier medium is prepared by mixing the componentsone with another. Compound A is then dissolved in the carrier medium bystirring. ³Refined oil = “refined glycerol-transesterified corn oil”,substantially glycerol free, as described in GB 2 257 359 and WO94/09211.

No phase separation or precipitation is observed for any of the abovecompositions 1 to 8 which are clear for 4 hours.

The Preferred Compounds of the Invention are safe for use in humans.Thus(2R,4S)-N-[1-(3,5-bistrifluoromethylbenzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl-quinolin-4-carboxamideis well tolerated in human at a dose of up to about 100 mg/kg or more,e.g. up to about 200 mg/kg.

On administration of Preferred Compounds of the Invention, in particularthe compound(2R,4S)-N-[1-(3,5-bistrifluoromethylbenzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl-quinolin-4-carboxamide,at doses as indicated above, e.g. at doses of 10 to 20 mg/day, apositive outcome is recorded with response rates for fibromyalgiatreatment at least equivalent to or comparable with those achieved withAmitryptilin and for CFS treatment at least equivalent to a 20%reduction in the score for one or more symptoms of CFS as describedabove.

1. A method of treating fibromyalgia or associated functional symptomsof fibromyalgia comprising administering to a patient in need thereof, a1-acylpiperidine substance P antagonist, the 1-acylpiperidine substanceP antagonist comprising a compound of formula

wherein X and Y are each independent of the other N and/or CH, and thering A is unsubstituted or mono- or poly-substituted by substituentsselected from the group consisting of lower alkyl, lower alkoxy,halogen, nitro and trifluoromethyl and for each compound,pharmaceutically-acceptable salts thereof.
 2. The method of treatmentaccording to claim 1, in which the compound is selected from the groupconsisting of(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-quinoline-4-carboxamide;(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-quinazoline-4-carboxamide;(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-quinoline-4-carboxamide;(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidinyl]-quinazoline-4-carboxamide;(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidinyl]-isoquinoline-1-carboxamide;and(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-nitro-benzyl)-piperidinyl]-quinazoline-4-carboxamideand for each compound, salts thereof.
 3. The method of treatmentaccording to claim 2 in which such compound is(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-quinoline-4-carboxamide.4. The method of treatment according to claim 1 comprising administeringsuch compound to such patient at a dose of about 1 to about 40 mg/kg perday.
 5. The method of treatment according to claim 4 comprisingadministering such compound to such patient at a dose of about 10 toabout 20 mg/kg per day.
 6. The method of treatment according to claim 1comprising administering such compound to such patient orally.
 7. Themethod of treatment according to claim 6 comprising administering suchcompound to such patient in the form of a tablet or a gelatin capsule.8. The method of treatment according to claim 2 comprising administeringsuch compound to such patient at a dose of about 1 to about 40 mg/kg perday.
 9. The method of treatment according to claim 8 comprisingadministering such compound to such patient at a dose of about 10 toabout 20 mg/kg per day.
 10. The method of treatment according to claim 2comprising administering such compound to such patient orally.
 11. Themethod of treatment according to claim 10 comprising administering suchcompound to such patient in the form of a tablet or a gelatin capsule.12. The method of treatment according to claim 3 comprisingadministering such compound to such patient at a dose of about 1 toabout 40 mg/kg per day.
 13. The method of treatment according to claim12 comprising administering such compound to such patient at a dose ofabout 10 to about 20 mg/kg per day.
 14. The method of treatmentaccording to claim 3 comprising administering such compound to suchpatient orally.
 15. The method of treatment according to claim 14comprising administering such compound to such patient in the form of atablet or a gelatin capsule.
 16. A method of treating fibromyalgia orassociated functional symptoms of fibromyalgia comprising: administeringto a patient in need thereof a compound selected from the groupconsisting of(2R,4S)-N-[1-(3,5-bisfluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]-4-oxo-4H-1-benzopyran-2-carboxamide;(2R,4S)-N-[1-(3,5-bisfluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-4-oxo-4H-1-benzopyran-2-carboxamide;and(2R,4S)-N-[1-(3,5-bisfluoromethyl-benzoyl)-2-(4-chlorobenzyl)-piperidin-4-yl]-6-fluoro-4-oxo-4H-1-benzopyran-2-carboxamide,and pharmaceutically-acceptable salts thereof.
 17. The method oftreatment according to claim 16 comprising administering such compoundto such patient at a dose of about 1 to about 40 mg/kg per day.
 18. Themethod of treatment according to claim 17 comprising administering suchcompound to such patient at a dose of about 10 to about 20 mg/kg perday.
 19. The method of treatment according to claim 16 comprisingadministering such compound to such patient orally.
 20. The method oftreatment according to claim 19 comprising administering such compoundto such patient in the form of a tablet or a gelatin capsule.